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1.
PLoS One ; 16(11): e0259306, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34784362

RESUMO

BACKGROUND: Vulvovaginal candidiasis is a common superficial candidiasis; however, a host's immunological mechanism against vaginal Candida infection remains unknown. OBJECTIVES: In this study, we aimed to elucidate the effect of iNKT cell activation on vulvovaginal candidiasis. METHODS: Using a vulvovaginal candidiasis model with estrogenized mice, we evaluated the fungal burden and number of leukocyte infiltrations in the vaginal lavage of wild-type C57BL/6J mice after Candida albicans inoculation. One day before C. albicans inoculation, α-galactosylceramide (the α-GalCer group) or sterile phosphate-buffered saline (the sham group) was intraperitoneally injected into the mice. We also evaluated the level of antimicrobial peptide S100A8 in the vaginal lavage and analyzed the correlation between S100A8 concentration and the number of vaginal leukocyte infiltrations. Moreover, the number of uterine and vaginal immune cells were evaluated using flow cytometry. RESULTS: The number of vaginal leukocyte infiltrations was significantly higher in the α-GalCer group than in the sham group 3 days after C. albicans inoculation. In addition, the fungal burden was significantly lower in the α-GalCer group than the sham group at 7 days after inoculation. In the analysis of S100A8 concentration of vaginal lavage, there were no significant differences between these two groups, although S100A8 concentration and the number of vaginal leukocyte infiltrations were positively correlated in the α-GalCer group. Moreover, the number of vaginal iNKT cells, NK cells and CD8+ T-cells was significantly higher in the α-GalCer group 3 days after inoculation. CONCLUSIONS: α-GalCer-stimulated iNKT cells likely play a protective role against vulvovaginal candidiasis.

2.
Antimicrob Agents Chemother ; : AAC0163021, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34780271

RESUMO

There are few reports on the clinical course of proven invasive aspergillosis (IA) due to rare/cryptic species in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. We retrospectively reviewed the electronic medical records of patients who underwent allo-HSCT between January 2012 and December 2018. Of 934 allo-HSCT recipients, 10 were diagnosed with proven IA and 61 were diagnosed with probable IA. DNA sequencing was performed in cases of proven IA, and Aspergillus could be identified to the species level in 8 of the 10 cases. Three were due to A. fumigatus, and 5 were due to rare/cryptic Aspergillus species, namely, A. turcosus, A. felis, A. viridinutans, A. nidulans, and A. calidoustus. In these 8 patients, no patients with IA due to A. fumigatus died, whereas 3 of the 5 with IA due to rare/cryptic species died within 12 weeks. The 2 surviving cases of IA due to rare/cryptic species were treated with surgical resection and antifungal treatment. Susceptibility testing for cryptic species in 4 cases showed an amphotericin B minimum inhibitory concentration (MIC) > 1 mg/L in 3 cases, itraconazole MIC > 1 mg/L in 2 cases, and voriconazole MIC > 1 mg/L in 2 cases. In conclusion, more than half of the causative pathogens of proven IA were rare/cryptic species, so it is important to accurately identify the Aspergillus species. In addition, surgical treatment might be an important option in cases of proven IA, given the possibility that the causative organisms are azole-resistant A. fumigatus or rare/cryptic species.

3.
Kurume Med J ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34544939

RESUMO

Febrile neutropenia, a serious complication that can occur during the treatment of hematological malignancies, can sometimes be fatal owing to fungal infection. Prospective randomized trials indicated the utility of liposomal amphotericin B or caspofungin as an empirical antifungal therapy. Itraconazole, a broad-spectrum tri azole antifungal agent, is poorly absorbed in the intestines after oral absorption and makes it difficult to achieve a stable serum drug concentration. Therefore, an intravenous formulation might offer a potentially safer and more effective alternative. To compare the efficacy and safety of empirical antifungal therapy, patients will be randomly assigned to either the liposomal amphotericin B 3.0 mg/kg once daily group or the intravenous itraconazole 200 mg dose group with five stratification factors (disease risk, previous antifungal prophylaxis, age, sex, and institute). The primary endpoint will be overall favorable response, comprising five secondary endpoints: successful treatment of baseline infection by the end of the treatment; absence of breakthrough infection; no discontinuation of the antifungal treatment due to drug-related toxicity; fever resolution during neutropenia; and 7-day survival after termination of the antifungal treatment. The target sample size of 850 subjects is sufficient to prove the non inferiority of itraconazole compared with liposomal amphotericin B, with a non-inferiority margin of 10%, one sided significance level of 5%, and power of 90%.

4.
PLoS Med ; 18(7): e1003660, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34228712

RESUMO

BACKGROUND: Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials. METHODS AND FINDINGS: A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d-1 (95% CI: 1.06 to 1.27 d-1), 0.777 d-1 (0.716 to 0.838 d-1), and 0.450 d-1 (0.378 to 0.522 d-1) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. CONCLUSIONS: In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tamanho da Amostra , Humanos , Modelos Biológicos , SARS-CoV-2 , Resultado do Tratamento , Carga Viral , Replicação Viral , Eliminação de Partículas Virais
5.
Med Mycol ; 59(10): 980-984, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34019670

RESUMO

Triazole-resistant Aspergillus fumigatus is a global health concern. In general, each triazole resistance pattern caused by the specified amino acid substitution of Cyp51A has a typical pattern depending on the mutation site. We evaluated the contribution of both Cyp51A and Hmg1 mutations to atypical triazole resistance in A. fumigatus. We used clinical triazole-resistant A. fumigatus strains collected in Japan and investigated the sequences of cyp51A and hmg1 genes. To delineate the association between the hmg1 mutation and atypical triazole resistance, the mutant hmg1 alleles in clinical multi-azole resistant strains were replaced with the wild-type hmg1 allele by CRISPR/Cas9 system. In our study, the combination of Cyp51A mutation and Hmg1 mutation was shown to additively contribute to triazole resistance. We also demonstrated that the triazole resistance conferred by the Hmg1 mutation showed a different pattern depending on the mutation site, similar to the Cyp51A mutation. Our results indicate that focusing on the phenotypes of multiple genes is essential to clarify the overall picture of the triazole resistance mechanism of A. fumigatus. LAY SUMMARY: The number of triazole-resistant Aspergillus fumigatus is increasing. We confirmed thatmutation in a hydroxymethylglutaryl-CoA reductase (Hmg1) in the fungus contributesto the resistance separately from Cyp51A mutation, and that susceptibility patterns aredifferent based on mutation site.

6.
Mycoses ; 64(8): 851-859, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34028893

RESUMO

BACKGROUND: Although fungi are found relatively easily by microscopic examination of pathological samples, identification of fungal genus and species in pathological samples is not easy because the morphological features of fungi are similar among genera and species. OBJECTIVES: A multiple real-time PCR was developed for identification of fungal genus/species, and morphological characterizations of fungi were analysed in pathological samples. PATIENTS/METHODS: Seventy-five formalin-fixed paraffin-embedded (FFPE) samples morphologically proven to contain any fungus were examined. A multiple real-time PCR system was developed to identify 25 fungal genus/species in pathological samples. Morphology of fungus in the specimens was re-reviewed retrospectively based on the results of real-time PCR. RESULTS: Real-time PCR identified fungal genus/species in 56 of 75 (74.6%) specimens with histologically proven fungal infection. In 53 specimens of filamentous fungi, Aspergillus spp. (22 specimens), Cladosporium (8), Scedosporium apiospermum (4), Malassezia sympodialis (1) and Candida albicans (1) were identified. Pseudohyphae of Candida were confused with filamentous fungus in a case. Morphological observation suggested differences in the presence of septated or non-septated hyphae, the filament size, and the branch angle among genus/species of filamentous fungi; however, genus/species was not able to be determined by their morphological features. In 22 specimens of yeasts, real-time PCR allowed for the identification of Candida albicans (12 specimens), Candida glabrata (2), Cladosporium (2), Scedosporium apiospermum (2), Pichia kudriavzevii (1) and Aspergillus sydowii (1). CONCLUSIONS: These data suggest that it is difficult to identify fungal genus/species by morphological features alone. Real-time PCR is useful to identify fungal genus/species in pathological samples.


Assuntos
DNA Fúngico/genética , Formaldeído , Fungos/genética , Fungos/isolamento & purificação , Micoses/microbiologia , Inclusão em Parafina , Feminino , Fungos/classificação , Humanos , Técnicas de Diagnóstico Molecular , Reação em Cadeia da Polimerase Multiplex , Micoses/patologia , Estudos Retrospectivos
7.
Trials ; 22(1): 309, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910617

RESUMO

OBJECTIVES: The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. TRIAL DESIGN: The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. PARTICIPANTS: Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO2 < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator INTERVENTION AND COMPARATOR: Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). MAIN OUTCOMES: The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. RANDOMIZATION: Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). BLINDING (MASKING): Only the assessors of the primary outcome will be blinded (blinded outcome assessment). NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman's equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. TRIAL STATUS: Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
COVID-19 , Infecções por HIV , COVID-19/tratamento farmacológico , Vacinas contra COVID-19 , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Nelfinavir/efeitos adversos , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Resultado do Tratamento
8.
J Fungi (Basel) ; 7(4)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923727

RESUMO

This systematic review and meta-analysis examined the optimal trough concentration of voriconazole for adult patients with invasive fungal infections. We used stepwise cutoffs of 0.5-2.0 µg/mL for efficacy and 3.0-6.0 µg/mL for safety. Studies were included if they reported the rates of all-cause mortality and/or treatment success, hepatotoxicity, and nephrotoxicity according to the trough concentration. Twenty-five studies involving 2554 patients were included. The probability of mortality was significantly decreased using a cutoff of ≥1.0 µg/mL (odds ratio (OR) = 0.34, 95% confidence interval (CI) = 0.15-0.80). Cutoffs of 0.5 (OR = 3.48, 95% CI = 1.45-8.34) and 1.0 µg/mL (OR = 3.35, 95% CI = 1.52-7.38) also increased the treatment success rate. Concerning safety, significantly higher risks of hepatotoxicity and neurotoxicity were demonstrated at higher concentrations for all cutoffs, and the highest ORs were recorded at 4.0 µg/mL (OR = 7.39, 95% CI = 3.81-14.36; OR = 5.76, 95% CI 3.14-10.57, respectively). Although further high-quality trials are needed, our findings suggest that the proper trough concentration for increasing clinical success while minimizing toxicity is 1.0-4.0 µg/mL for adult patients receiving voriconazole therapy.

9.
Eur J Immunol ; 51(9): 2281-2295, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33728652

RESUMO

Cryptococcus gattii is a capsular pathogenic fungus causing life-threatening cryptococcosis. Although the capsular polysaccharides (CPs) of C. gattii are considered as virulence factors, the physiological significance of CP biosynthesis and of CPs themselves is not fully understood, with many conflicting data reported. First, we demonstrated that CAP gene deletant of C. gattii completely lacked capsule layer and its virulence, and that the strain was susceptible to host-related factors including oxidizing, hypoxic, and hypotrophic conditions in vitro. Extracellular CPs recovered from culture supernatant bound specifically to C. gattii acapsular strains, not to other fungi and immune cells, and rendered them the immune escape effects. In fact, dendritic cells (DCs) did not efficiently uptake the CP-treated acapsular strains, which possessed no visible capsule layer, and a decreased amount of phosphorylated proteins and cytokine levels after the stimulation. DCs recognized C. gattii acapuslar cells via an immune receptor CD11b- and Syk-related pathway; however, CD11b did not bind to CP-treated acapsular cells. These results suggested that CPs support immune evasion by coating antigens on C. gattii and blocking the interaction between CD11b and C. gattii cells. Here, we describe the importance of CPs in pathogenicity and immune evasion mechanisms of C. gattii.


Assuntos
Antígeno CD11b/imunologia , Cryptococcus gattii/imunologia , Cápsulas Fúngicas/imunologia , Polissacarídeos Fúngicos/imunologia , Evasão da Resposta Imune/imunologia , Quinase Syk/metabolismo , Animais , Criptococose/imunologia , Cryptococcus gattii/genética , Cryptococcus gattii/patogenicidade , Citocinas/biossíntese , Células Dendríticas/imunologia , Feminino , Cápsulas Fúngicas/genética , Polissacarídeos Fúngicos/genética , Deleção de Genes , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/genética , Polissacarídeos/imunologia , Fatores de Virulência/imunologia
10.
Rinsho Ketsueki ; 62(1): 51-54, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33551426

RESUMO

An 80 year old male who had received immunosuppressive therapy for myelodysplastic syndrome presented with fever, fatigue, and elevated serum Aspergillus antigen. Computed tomography revealed infiltrative shadows in the left lower lung and subcutaneous nodules. A polymerase chain reaction assay from lung and subcutaneous nodule samples identified the presence Aspergillus udagawae. A. udagawae is a cryptic species that shares similar morphological characteristics with A. fumigatus but genetically differs from the latter in its susceptibility to antifungal drugs. When immunosuppressed patients with hematological malignancies develop disseminated aspergillosis, biopsy and fungal tests are crucial to identify the causative fungus, including cryptic species, for deciding the appropriate therapeutic intervention.


Assuntos
Aspergilose , Síndromes Mielodisplásicas , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Aspergilose/complicações , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergillus , Humanos , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico
11.
Infection ; 49(4): 775-779, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33156492

RESUMO

BACKGROUND: The pathogenic fungus Schizophyllum sp. can cause allergic fungal rhinosinusitis and allergic bronchopulmonary mycosis in humans. Sinus and lung infections due to Schizophyllum sp. have been reported globally; however, no case of hypertrophic pachymeningitis due to this pathogen has been reported yet. Herein, we describe for the first time, a case of hypertrophic pachymeningitis due to Schizophyllum sp. CASE PRESENTATION: A 69-year-old woman visited the hospital with chief complaints of headache, right trigeminal neuralgia (third branch), ataxic gait, and deafness in the right ear. Magnetic resonance imaging revealed a tumor in the right sphenoidal sinus and thickening of the dura mater surrounding the right porus acusticus internus. Endoscopic sinus surgery and neuroendoscopic biopsy were performed to remove sinus lesions and intracranial lesions, respectively. Both pathological specimens showed findings indicative of filamentous fungi on Grocott's staining. DNA sequencing with the sinus specimen revealed Schizophyllum sp. as the causative pathogen, consistent with the diagnosis of fungal sinusitis and hypertrophic pachymeningitis. Intravenous liposomal amphotericin B was started, but owing to lack of improvement, the treatment was switched to intravenous voriconazole. We observed improvements in both radiological findings and symptoms. However, the symptoms exacerbated again when the trough level of voriconazole decreased. Upon increasing the voriconazole dose, a higher trough level was obtained and the symptoms improved. CONCLUSION: Our study suggests that when symptoms of central nervous system infection due to Schizophyllum sp. do not improve with liposomal amphotericin B, voriconazole can be administered at high trough levels to improve the symptoms.

12.
Infection ; 49(1): 165-170, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32720129

RESUMO

A 42-year-old man diagnosed with acute myeloid leukemia complained of progressive swelling of the right side of his face with pain 11 days after the third cycle of consolidation therapy with high-dose arabinosylcytosine-cytarabine. Head and neck magnetic resonance imaging showed a mass lesion in his right maxillary sinus with parapharyngeal involvement, which included the right masseter muscle, intraorbital involvement, and an abscess in his brain. Chest computed tomography revealed peribronchial small nodules in his right upper lobe and a necrotic tumor in his right lower lobe. Molds identified as Cunninghamella bertholletiae were isolated from the necrotic ulcer. According to these results, chemotherapy for leukemia was discontinued. High-dose liposomal amphotericin (10 mg/kg/day) was initiated. Because renal dysfunction occurred, the dosage was decreased to 6 mg/kg and combined with 150 mg/day micafungin. Debridement of necrotic tissue in the right maxillary sinus and establishment of the fenestration between the sinus and oral cavity were performed. Subsequently, brain and lung lesions were surgically removed. Rhinocerebral mucormycosis was successfully treated without relapse over 3 years by a 112-day course of intravenous anti-fungal therapy and 223-day course of terbinafine and partial surgical removal, respectively, to maintain masticatory and ocular functions. To our knowledge, there has been no other report of a long-term survival case of rhinocerebral mucormycosis due to C. bertholletiae.


Assuntos
Infecções Fúngicas do Sistema Nervoso Central , Cunninghamella , Leucemia Mieloide Aguda , Pneumopatias Fúngicas , Mucormicose , Adulto , Antifúngicos/uso terapêutico , Antineoplásicos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Pulmão/patologia , Masculino
13.
J Infect Chemother ; 27(3): 480-485, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33189538

RESUMO

INTRODUCTION: Influenza remains a clinically heavy burden worldwide. The objective of this study was to clarify clinical manifestations of severely ill patients infected with influenza. METHODS: The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2019 (5 influenza seasons) using an internet-surveillance system. RESULTS: A total of 924 patients were enrolled and analyzed. The median age was 78 years (IQR, 67-84), and the patients in the 2015-2016 season were significantly younger than those in other seasons. Pneumonia was the most common disease indicated as a cause for hospitalization, followed by a poor general condition and exacerbation of underlying respiratory diseases. Antiviral drugs were administered in 97.0% of the patients with peramivir being the most-frequently use antiviral. In-hospital death was recorded for 44 patients (4.8%). Multivariate analysis indicated that nursing home resident (OR: 6.554) and obesity (OR: 24.343) were independent predictors of in-hospital mortality. CONCLUSIONS: Complications of influenza infection remain a heavy burden especially among the elderly. Continuous nationwide surveillance will be required to grasp the actual situation of influenza epidemics. (UMIN000015989).


Assuntos
Influenza Humana , Adulto , Idoso , Mortalidade Hospitalar , Hospitalização , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Internet , Japão/epidemiologia , Estudos Prospectivos , Estações do Ano
14.
PLoS One ; 15(12): e0243223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33264362

RESUMO

BACKGROUND: Candida auris infections have recently emerged worldwide, and this species is highly capable of colonization and is associated with high levels of mortality. However, strain-dependent differences in colonization capabilities and virulence have not yet been reported. OBJECTIVES: In the present study, we aimed to clarify the differences between clinically isolated invasive and non-invasive strains of C. auris. METHODS: We evaluated colonization, dissemination, and survival rates in wild C57BL/6J mice inoculated with invasive or non-invasive strains of C. auris under cortisone acetate immunosuppression, comparing with those of Candida albicans and Candida glabrata infections. We also evaluated the potency of biofilm formation. RESULTS: Stool fungal burdens were significantly higher in mice inoculated with the invasive strains than in those infected with the non-invasive strain. Along with intestinal colonization, liver and kidney fungal burdens were also significantly higher in mice inoculated with the invasive strains. In addition, histopathological findings revealed greater dissemination and colonization of the invasive strains. Regarding biofilm-forming capability, the invasive strain of C. auris exhibited a significantly higher capacity of producing biofilms. Moreover, inoculation with the invasive strains resulted in significantly greater loss of body weight than that noted following infection with the non-invasive strain. CONCLUSIONS: Invasive strains showed higher colonization capability and rates of dissemination from gastrointestinal tracts under cortisone acetate immunosuppression than non-invasive strains, although the mortality rates caused by C. auris were lower than those caused by C. albicans.


Assuntos
Candida/fisiologia , Candidíase Invasiva/patologia , Candidíase/patologia , Trato Gastrointestinal/microbiologia , Animais , Biofilmes/crescimento & desenvolvimento , Candida/patogenicidade , Candida albicans/patogenicidade , Candida albicans/fisiologia , Candida glabrata/patogenicidade , Candida glabrata/fisiologia , Candidíase/microbiologia , Candidíase Invasiva/microbiologia , Trato Gastrointestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Virulência
16.
J Infect Chemother ; 26(11): 1232-1236, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32828679

RESUMO

Because exclusive use of echinocandins can induce the drug-resistant strains, appropriate use of azoles and polyenes is still necessary in the treatment of candidemia. In this study, we conducted a meta-analysis of randomized controlled trials regarding the efficacy and safety of azole and polyene antifungals in the treatment of candidemia. MEDLINE and the Cochrane Register of Controlled Trials were used as reference databases, and papers published up to June 10, 2019 were searched. The search results were carefully scrutinized, duplicate references were removed, and the study was ultimately carried out using three reports. Among azole antifungals, fluconazole and voriconazole were extracted, however; only conventional amphotericin B (AMPH-B) was extracted among polyene antifungals. Treatment successes with the use of azoles and AMPH-B were compared, and findings showed that AMPH-B was significantly superior (RR = 0.90, 95% CI 0.82-1.00, p = 0.04). However, there was no significant difference in mortality (RR = 0.87, 95% CI 0.72-1.07, p = 0.19). Analysis of adverse events showed that renal disorders were significantly less common with azoles than with AMPH-B (RR = 0.26, 95% CI 0.10-0.68, p = 0.006). In conclusion, AMPH-B were superior to azoles in terms of efficacy, but had a risk of causing renal disorders.


Assuntos
Anfotericina B , Candidemia , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Azóis/efeitos adversos , Candidemia/tratamento farmacológico , Equinocandinas , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
J Infect Chemother ; 26(11): 1164-1176, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32620421

RESUMO

INTRODUCTION: Echinocandins are frequent use antifungals in the treatment of invasive candidiasis, and it is important to update information on their efficacy and safety for optimal antifungal drug treatment. The aim of this study is to clarify whether echinocandins are superior to non-echinocandins for the treatment of invasive candidiasis. METHODS: We conducted a meta-analysis of RCTs of echinocandins and non-echinocandins for adult invasive candidiasis. The MEDLINE, Web of Sciences, Cochrane Register of Controlled Trials, and ClinicalTrials.gov databases before June 2019 were used. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated using the Mantel-Haenszel method random-effects model. RESULTS: We identified 14,846 articles and screened, and five studies were included meta-analysis. The treatment success ratio for echinocandins was significantly higher than that for non-echinocandins (RR = 1.14, 95% CI 1.06-1.22, p = 0.0003). In regard to adverse events, there was no significant difference between the two treatment groups. A subgroup analysis showed that the treatment success ratio for echinocandins was significantly higher than that for azoles (RR = 1.20, 1.08-1.34, p = 0.001), whereas no significant differences were observed between echinocandins and polyenes. In safety analysis, the incidence ratio of electrolyte disorder (RR = 0.50, 0.33-0.76, p = 0.001), renal disorder (RR = 0.19, 0.09-0.40, p < 0.0001), and fever (RR = 0.46, 0.23-0.93, p = 0.03) were significantly lower in patients receiving echinocandins than in those receiving polyenes. CONCLUSIONS: This meta-analysis based on RCTs was first to show that use of echinocandins was associated with improved clinical success. Echinocandins may be useful as a first-line drug for invasive candidiasis.


Assuntos
Candidíase Invasiva , Equinocandinas , Adulto , Antifúngicos/efeitos adversos , Azóis , Candidíase Invasiva/tratamento farmacológico , Equinocandinas/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
J Infect Chemother ; 26(11): 1198-1204, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32682683

RESUMO

INTRODUCTION: Streptococcus pneumoniae is a commensal bacterium of the human nasopharynx and a major causative pathogen of bacterial diseases worldwide. Pilus of S. pneumoniae is one of the virulence factors which enhance the adhesion to the host epitherial cells in the upper respiratory tract. METHODS: We analyzed the serotype distribution and presence of pilus genes, rrgC and sipA, among 785 S. pneumoniae isolates from specimens of patients with invasive or non-invasive disease in a regional Japanese hospital between October 2014 and August 2018. We next performed multilocus sequence typing and penicillin-resistant genotyping for 86 isolates of serotype 35B. RESULTS: Serotype 35B was the most frequent serotype which accounted for 11.0% of total isolates and had pilus genes at high rate (80.2%). Clonal complex (CC) 558 isolates accounted for 77.9% of serotype 35B and were highly positive for rrgC and gPRSP (98.5%). In contrast, all CC2755 isolates (19.8%) were rrgC-negative and gPISP. CONCLUSIONS: Our results suggest that CC558 may assist the prevalence of serotype 35B after the introduction of vaccines, as that clone has pili as adhesins in addition to non-susceptibility against penicillin. These results may be useful information for development of optimal preventive strategies. Continuous studies on serotype distribution and virulence factors of S. pneumoniae are necessary.


Assuntos
Infecções Pneumocócicas , Vacinas Pneumocócicas , Humanos , Japão/epidemiologia , Tipagem de Sequências Multilocus , Infecções Pneumocócicas/epidemiologia , Infecções Pneumocócicas/prevenção & controle , Sorogrupo , Sorotipagem , Streptococcus pneumoniae/genética
19.
Mycoses ; 63(8): 779-786, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32510723

RESUMO

BACKGROUND: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy. OBJECTIVE: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy. METHODS: The target voriconazole trough concentration (Cmin ) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine Cmin cut-offs for AEs. RESULTS: A total of 401 patients were included. Among 108 patients with high initial Cmin , voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial Cmin , voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial Cmin was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with Cmin at the onset of AEs, and the Cmin cut-offs were 3.5 µg/mL for hepatotoxicity and 4.2 µg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms. CONCLUSIONS: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy.


Assuntos
Antifúngicos , Doença Hepática Induzida por Substâncias e Drogas , Voriconazol , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Gestão de Antimicrobianos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Monitoramento de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Estudos Retrospectivos , Voriconazol/administração & dosagem , Voriconazol/efeitos adversos , Voriconazol/uso terapêutico
20.
Mycoses ; 63(8): 794-801, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32391919

RESUMO

BACKGROUND: Fungal infections are a major complication of neutropaenia following chemotherapy. Their early diagnosis is difficult, and empirical antifungal treatment is widely used, and uses of less toxic drugs that reduce breakthrough infection are required. OBJECTIVE: We conducted a multicentre, open-label, randomised, non-inferiority trial to compare the safety and efficacy of intravenous itraconazole (ivITCZ) and liposomal amphotericin B (LAmB) as empirical antifungal therapy in patients with haematological malignancies with neutropaenia and persistent fever. METHODS: Patients with haematological malignancies who developed fever refractory to broad-spectrum antibacterial agents under neutropaenia conditions were enrolled. Patients were randomised for treatment with LAmB (3.0 mg/kg/d) or ivITCZ (induction: 400 mg/d, maintenance: 200 mg/d). RESULTS: Observed overall favourable response rates of 17/52 (32.7%) and 18/50 (36.0%) in the LAmB and ivITCZ groups, with a model-based estimate of a 4% difference (90% CI, -12% to 20%), did not fulfil the statistical non-inferiority criterion. In the LAmB group, there were two cases of breakthrough infection and five cases of probable invasive fungal disease, whereas in the itraconazole group, neither breakthrough infection nor probable invasive fungal disease occurred. Patients in the ivITCZ group had significantly fewer grade 3-4 hypokalaemia-related events than LAmB group patients (P < .01). The overall incidence of adverse events tended to be lower in the ivITCZ group (P = .07). CONCLUSION: ivITCZ showed similar efficacy and safety as LAmB as empirical antifungal therapy in haematological malignancy patients with febrile neutropaenia, although the small sample size and various limitations prevented demonstration of its non-inferiority.


Assuntos
Anfotericina B , Neutropenia Febril Induzida por Quimioterapia/complicações , Itraconazol , Micoses , Administração Intravenosa , Adulto , Idoso , Anfotericina B/administração & dosagem , Anfotericina B/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/patologia , Feminino , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/patologia , Humanos , Itraconazol/administração & dosagem , Itraconazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/etiologia , Adulto Jovem
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